Pathogenesis of nodding syndrome; Preliminary findings

Objective Nodding syndrome (NS) is an epileptic encephalopathy characterized by head-nodding. The pathogenesis is poorly understood but epidemiological studies have demonstrated a consistent association with Onchocerca volvulus. We hypothesized NS is a neuro-inflammatory disorder with antibodies to O.volvulus or its symbiont bacteria, Wolbachia, cross-reacting with neuronal proteins.

Method: We conducted a case-control study of 154 children with long-standing NS and 154 age-matched unaffected children (CC) in Uganda. O.volvulus seroreactivity was assessed by anti-Ov16 IgG. We also conducted a preliminary study of neuronal/glial antibodies in 50 CC-sera and 50 NS-sera/paired CSFs by immunohistochemistry on rat brain sections and immunofluorescence on cultured rat hippocampal neurons. The presence of antibodies to extracellular (LGI1, CASPR2, GABAaR, GABAbR) or intracellular (leiomodin-1) antigens was assessed by cell-based assays.

Result: Ov-16 IgG were detected in 95% NS vs 55% CC. Neuronal-reactive antibodies were found in 18/50(36%) NS sera bound principally to the Purkinje cells and the molecular layer of cerebellum, compared with 3/50(6%) CC sera. NS sera also bound to live neurons and to fixed/permeabilized neurons consistent with an intracellular target. Antibodies to specific antigens in NS sera included 8/50(16%) to GABAbR and 7(14%) GABAaR. In addition, 14/50(28%) NS sera (CC 18%) and 5/50(10%) NS CSF-bound to leiomodin-1 in fixed/permeabilised cells.

Conclusions: Antibodies to O.volvulus-specific antigens are more common in NS vs controls. Increased reactivity of NS sera with brain tissue is consistent with our hypothesis of O.volvulus-induced neuroreactive antibodies in NS. Furthermore, IgG reactivity of NS CSF with leiomodin-1 would support its use as NS biomarker.